Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist

Science. 2006 Dec 1;314(5804):1467-70. doi: 10.1126/science.1130471.

Abstract

Women with mutations in the breast cancer susceptibility gene BRCA1 are predisposed to breast and ovarian cancers. Why the BRCA1 protein suppresses tumor development specifically in ovarian hormone-sensitive tissues remains unclear. We demonstrate that mammary glands of nulliparous Brca1/p53-deficient mice accumulate lateral branches and undergo extensive alveologenesis, a phenotype that occurs only during pregnancy in wild-type mice. Progesterone receptors, but not estrogen receptors, are overexpressed in the mutant mammary epithelial cells because of a defect in their degradation by the proteasome pathway. Treatment of Brca1/p53-deficient mice with the progesterone antagonist mifepristone (RU 486) prevented mammary tumorigenesis. These findings reveal a tissue-specific function for the BRCA1 protein and raise the possibility that antiprogesterone treatment may be useful for breast cancer prevention in individuals with BRCA1 mutations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Estradiol / pharmacology
  • Estrous Cycle
  • Female
  • Genes, BRCA1*
  • Genes, p53
  • Hormone Antagonists / pharmacology*
  • Hormone Antagonists / therapeutic use
  • Humans
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / metabolism
  • Mammary Neoplasms, Animal / genetics
  • Mammary Neoplasms, Animal / prevention & control*
  • Mice
  • Mifepristone / pharmacology*
  • Mifepristone / therapeutic use
  • Mutation
  • Phosphorylation
  • Progesterone / antagonists & inhibitors*
  • Progesterone / pharmacology
  • Proteasome Endopeptidase Complex / metabolism
  • RNA, Small Interfering
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / genetics
  • Receptors, Progesterone / metabolism*
  • Ubiquitin / metabolism

Substances

  • Hormone Antagonists
  • RNA, Small Interfering
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Ubiquitin
  • Mifepristone
  • Progesterone
  • Estradiol
  • Proteasome Endopeptidase Complex